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Understanding the cellular behaviour of the luminescent lanthanide complexes

Abstract

The design of responsive optical cellular probes remains a key challenge for biology and medicine. Luminescent lanthanide complexes are well suited for this purpose, with their information-rich emission profiles, and long luminescence lifetimes which allow gating out of interfering background signals. In order to design complexes for in cellulo applications, it is important to gain a greater understanding of the cellular behaviour of such complexes. This thesis describes work performed to this end. The studies described herein utilise a broad range of complexes synthesised in Durham. These complexes comprise a Eu(^3+) or Tb(^3+) ion encapsulated in a cyclen macrocycle to which is attached a sensitising chromophore and two or three amide- or carboxylate-based pendant arms. The synthesis and characterisation of one set of such complexes is described. Modification of the pendant arm was shown to result in considerable variation of the complex helicity and structure, but with no alteration in the cellular behaviour. This thesis also describes work which was performed to explore various aspects of cellular behaviour. The range of observed sub-cellular localisations are described, structure-localisation relationships presented and the observation of nucleolar localisation in some cases investigated. Studies of uptake mechanisms indicated that all complexes are transported across the cell membrane by a common pathway of macropinocytosis. Examples of various sub-cellular speciation states are presented, with detailed investigation of one case of reversible protein binding which induces a helicity change in the complex in an enantioselective fashion. Finally, the effect of the complexes on the cellular homeostasis is discussed, with the finding that complexes do not generally perturb the normal function of the cell. This work therefore demonstrates that most luminescent lanthanide complexes do exhibit behaviour which makes them suitable for use as cellular probes. They are generally non-toxic, readily internalised and localise to specific organelles, and have demonstrated utility in reporting on the sub-cellular environment.